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The Bioequivalence Study of Two Different Formulations of Candesartan Cilexetil After a Single Oral Dose Administration Under Fasting Conditions

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ClinicalTrials.gov Identifier: NCT04012307
Recruitment Status : Completed
First Posted : July 9, 2019
Last Update Posted : November 18, 2019
Sponsor:
Collaborator:
Altasciences Company Inc.
Information provided by (Responsible Party):
Pharmtechnology LLC

Brief Summary:
This single dose study was designed in accordance with EMA (the European Medicines Agency) regulatory guidelines, with the aim of characterizing the bioavailability of candesartan in the two formulations in healthy subjects. As this is a bioequivalence trial where each subject received each study treatment in a crossover fashion, a control group was not included. Within the clinical portion of the study each subject received a single oral dose of the test and the reference formulation in compliance with the generated randomization code. The primary study endpoints were the pharmacokinetic (PK) parameters Cmax and AUC0-t of candesartan.

Condition or disease Intervention/treatment Phase
Bioequivalence Drug: Candesartan Cilexetil 32mg Drug: Atacand® PROTECT Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Masking Description: The randomization code will not be available to the personnel of the bioanalytical facility until the bioanalytical tables have been finalized and audited by the Quality Assurance (QA) department. Study participants will be aware they will receive different formulations of the same drug, without being informed which product (Test or Reference) is being administered.
Primary Purpose: Other
Official Title: Single Dose Crossover Comparative Bioavailability Study of Candesartan Cilexetil 32 mg Tablets in Healthy Adult Subjects Under Fasting Conditions
Actual Study Start Date : July 11, 2019
Actual Primary Completion Date : August 13, 2019
Actual Study Completion Date : August 14, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Sequence AB
20 subjects assigned to the sequence AB will receive a single 32 mg dose of the test product Candesartan Cilexetil (1 x 32 mg tablet), marked as A in the sequence, in Period 1 and a single 32 mg dose of the reference product Atacand® PROTECT (1 x 32 mg tablet), marked as B in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.
Drug: Candesartan Cilexetil 32mg
Candesartan Cilexetil is manufactured by Pharmtechnology LLC, Republic of Belarus. Each tablet contains 32 mg of candesartan cilexetil.
Other Name: The test product

Drug: Atacand® PROTECT
Atacand® PROTECT is manufactured by AstraZeneca GmbH, Germany. Each tablet contains 32 mg of candesartan cilexetil.
Other Name: The reference product

Sequence BA
20 subjects assigned to the sequence BA will receive a single 32 mg dose of the reference product Atacand® PROTECT (1 x 32 mg tablet), marked as B in the sequence, in Period 1 and a single 32 mg dose of the test product Candesartan Cilexetil (1 x 32 mg tablet), marked as A in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken.
Drug: Candesartan Cilexetil 32mg
Candesartan Cilexetil is manufactured by Pharmtechnology LLC, Republic of Belarus. Each tablet contains 32 mg of candesartan cilexetil.
Other Name: The test product

Drug: Atacand® PROTECT
Atacand® PROTECT is manufactured by AstraZeneca GmbH, Germany. Each tablet contains 32 mg of candesartan cilexetil.
Other Name: The reference product




Primary Outcome Measures :
  1. Cmax of candesartan in plasma after administration of the test and the reference products. [ Time Frame: Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration. ]
    Maximum observed concentration in plasma.

  2. AUC0-t of candesartan in plasma after administration of the test and the reference products. [ Time Frame: Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration. ]
    Cumulative area under the concentration time curve calculated from 0 to time of last observed quantifiable concentration (TLQC) using the linear trapezoidal method.


Secondary Outcome Measures :
  1. Tmax of candesartan in plasma after administration of the test and the reference products. [ Time Frame: Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration. ]
    Time of maximum observed concentration; if it occurs at more than one time point, Tmax is defined as the first time point with this value.

  2. TLQC of candesartan in plasma after administration of the test and the reference products. [ Time Frame: Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration. ]
    Time of last observed quantifiable concentration.

  3. AUC0-INF of candesartan in plasma after administration of the test and the reference products. [ Time Frame: Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration. ]
    Area under the concentration time curve extrapolated to infinity, calculated as AUC0-t + ĈLQC (the predicted concentration at time TLQC) / λZ (apparent elimination rate constant).

  4. Residual area of candesartan in plasma after administration of the test and the reference products. [ Time Frame: Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration. ]
    Extrapolated area (i.e. percentage of AUC0-INF due to extrapolation from TLQC to infinity).

  5. Time point where the log-linear elimination phase begins (TLIN) of candesartan in plasma after administration of the test and the reference. products. [ Time Frame: Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration. ]
    Time point where the log-linear elimination phase begins.

  6. λZ of candesartan in plasma after administration of the test and the reference products. [ Time Frame: Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration. ]
    Apparent elimination rate constant, estimated by linear regression of the terminal linear portion of the log concentration versus time curve.

  7. Terminal elimination half-life (Thalf) of candesartan in plasma after administration of the test and the reference products. [ Time Frame: Time points 0.00 (prior to each drug administration) and 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration. ]
    Terminal elimination half-life, calculated as ln(2)/λZ.

  8. Number of treatment-emergent adverse events for the test and the reference products. [ Time Frame: Up to 11 days (after the first drug administration until the end of the period of 1 day following the last blood sample of the study) ]
    The safety population will include all subjects who received at least one dose of the test or the reference product. Any significant changes will be recorded as treatment-emergent adverse events only if they are judged clinically significant by the qualified investigator or delegate.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Provision of signed and dated informed consent form (ICF)
  2. Stated willingness to comply with all study procedures and availability for the duration of the study
  3. Healthy Caucasian adult male or female
  4. If female, meets one of the following criteria:

(1) Physiological postmenopausal status, defined as the following:

a) absence of menses for at least one year prior to the first study drug administration (without an alternative medical condition); and b) Follicle stimulating hormone (FSH) levels ≥ 40 mIU/mL at screening; or (2) Surgical postmenopausal status, defined as the following:

  1. bilateral oophorectomy; and
  2. absence of menses for at least 90 days prior to the first study drug administration; and
  3. FSH levels ≥ 40 mIU/mL at screening; or (3) Hysterectomy with FSH levels ≥ 40 mIU/mL at screening If postmenopausal and has an FSH of < 40 mIU/mL, but meets all other criteria in (1), (2) or (3) above as well as all the other inclusion criteria, screening estradiol serum level must be equal to or below 150 pmol/L. In the case of hysterectomy, if FSH and estradiol do not meet the criteria, eligibility for study participation will be based on medical judgment.

    5. Aged at least 18 years but not older than 55 years

    6. Body mass index (BMI) within 18.5 kg/m2 to 30.0 kg/m2, inclusively

    7. Non- or ex-smoker (An ex-smoker is defined as someone who completely stopped using nicotine products for at least 180 days prior to the first study drug administration)

    8. Clinical laboratory values within the laboratory's stated normal range; if not within this range, they must be without clinical significance, as determined by an investigator

    9. Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on the physical examination (including vital signs) and/or ECG, as determined by an investigator

    Exclusion Criteria:

    1. Female who is lactating at screening
    2. Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration
    3. Seated pulse rate less than 50 Beats per Minute (bpm) at the screening visit and prior to the first study drug administration
    4. Seated blood pressure below 110/60 mmHg at the screening visit and prior to the first study drug administration
    5. History of significant hypersensitivity to candesartan or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs
    6. Presence or history of significant gastrointestinal, liver or kidney disease, or any other condition (including but not limited to cholecystectomy) that is known to interfere with drug absorption, distribution, metabolism or excretion, or known to potentiate or predispose to undesired effects
    7. History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease
    8. Presence of clinically significant ECG abnormalities at the screening visit, as defined by medical judgment
    9. History of rare hereditary problems of galactose and/or lactose intolerance, lactase deficiency or glucose-galactose malabsorption
    10. Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic)
    11. Any clinically significant illness in the 28 days prior to the first study drug administration
    12. Use of any prescription drugs (with the exception of hormone replacement therapy) in the 28 days prior to the first study drug administration, that in the opinion of an investigator would put into question the status of the participant as healthy
    13. Any history of tuberculosis
    14. Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration
    15. Positive screening results to HIV Ag/Ab Combo, Hepatitis B surface Antigen (HBsAG) or Hepatitis C Virus (HCV) tests
    16. Inclusion in a previous group for this clinical study
    17. Intake of candesartan in the 28 days prior to the first study drug administration
    18. Intake of an Investigational Product (IP) in the 28 days prior to the first study drug administration
    19. Donation of 50 mL or more of blood in the 28 days prior to the first study drug administration
    20. Donation of 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical studies, etc.) in the 56 days prior to the first study drug administration

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04012307


Locations
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Canada, Quebec
Altasciences Company Inc.
Mont-Royal, Quebec, Canada, H3P 3P1
Sponsors and Collaborators
Pharmtechnology LLC
Altasciences Company Inc.
Investigators
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Principal Investigator: Eric Sicard, MD Altasciences Company Inc.

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Responsible Party: Pharmtechnology LLC
ClinicalTrials.gov Identifier: NCT04012307     History of Changes
Other Study ID Numbers: PTL-P8-977 (v.1.3 06/26/2019)
First Posted: July 9, 2019    Key Record Dates
Last Update Posted: November 18, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pharmtechnology LLC:
Candesartan Cilexetil
Bioequivalence
Atacand PROTECT
Additional relevant MeSH terms:
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Candesartan
Candesartan cilexetil
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action